Cyclic ketones



nited States Fatent CYCLIC KETONES Howard R. Guest, Charleston, andHarry A. Stan'slmry,

In, South Charleston, W. Va., assignors to Union Carbide Corporation, acorporation of New York No Drawing. Original application June 23, 1953,Ser. No. 363,688, now Patent No. 2,891,888, dated June 23, 1959. Dividedand this application May 7, 1958, Ser. No. 733,488

2 Claims. (Cl. 260-586) This invention relates to insecticides closelyrelated to those found in pyrethrum flowers, Chrysanthemumcinerariaefolium. More particularly, it is concerned with3-(2cyclopentenyl)-2-methyl 4 oxo 2 cyclopentenyl chrysanthemumate as anew composition of matter. The structure of this ester, to which thename cyclethrin following formula,

themumate C C-0HC C I con. CHr-CH, 3- 2-cyclopentenyl-2-methyl-4-oxo-2-cyclopenteuyl ch ryaanone oon c omon=o1n+mo water 0 CH:

allethrin The application to this alcohol and this acid of conventionalprocedures for forming an ester, involving as theydo elevatedtemperatures and long reaction periods, results in deterioration of thecyclopentenolone molecule and poor yields of allethrin. The processsuggested by La Forge and others (J. Org. Chem, vol. 12, pp. 199-202(1947); J. Chem. Soc. (1950, pp. 3552-63), employs the acid chloridemade by the action of thionyl chloride upon the acid. The acid chloridein turn is reacted with the cyclopentenolone in the presence of pyridineto give has been applied, can be represented graphically by the containthe extract of twenty pounds of pyrethrum flowers I to the gallon ofsolvent, such as petroleum oil distillate. This conncentrate could thenbe diluted toa pyrethrin content of about 0.05 to 0.25 percent by weightfor a household spray. Because of the high cost, of pyrethrins andbecause the action of pyrethrins tends, at use levels, toward paralysisrather than outright killing, theyare supplemented with rotenone,thiocyanates, DDT and related materials and to provide kill. Suchmixtures give both kill and knockdown.

Until the synthesis of allethr-in in the laboratories of the Departmentof Agriculture, pyrethrum-was unique in its rapid paralytic propertiesand freedom from hazard to mammalian organisms and the only material ofits type which could be used to provide rapid knockdown (paralysis) offlies. Two of the active constituents of pyrethrum flowers are esters ofsubstituted 3-methyl-2- cyclopenten-4-ol-l-ones andchrysanthemummonocarb'oxylic acid. In the procedure employed for thesynthesis of allethrin, chrysanthemummonocarboxylic acid and 2-allyl-3-methyl-2-cyclopenten-4-ol-1-one are each prepared separately bya series of steps, followed by the formation of the ester from these twocomponents. The following allethrin. A number of difiiculties over andabove those arising out of the corrosive nature of the thionyl chlorideand the noxious qualities of the sulfur dioxide and hydrogen chlorideevolved areencountered in this final step of making allethrin. Forinstance, certain coproduct alcohol impurities present in the2-allyl-3-methyl 2- cyclopenten-4-ol-1-one are also esterified by theacid chloride treatment. The resulting ester impurities in the allethrinare of-low insecticidal activity and very difiicult to remove fromtheallethrin. In addition, sulfur and chlonine compounds of unknownstructure are formed and remain as impurities in the allethrin. In thisconnection, it is relevant to note that there is a definitedisinclination on the part of the Federal Food and Drug Administrationto allow more than traces of such'impurities in material which ispresented for use as a safe insecticide.

The difficulties. and shortcomings of the acid chloride procedure havebeen obviated by the use ofchrysanthemumrnonocarboxylic acid anhydridein the esterification step for the production of allethri'n' and otheresters. This improvement is the subject of the copending applicationSerial No. 299,729, filed. July 18, 1952, now US. Patent No. 2,768,965.

By reason of the numerous steps required for the synthesis ofchrysanthemummonocarboxylic acid and2-allyl-3-methyl-2-cyclopenten-4-ol-l-one, and also the complicatednature of the operations, allethrin is and i'slikely to remain a highcost chemical for use in household-type oil sprays. Currently, the priceof allethrin is about three-fifths the price of pyrethrins. Pyrethrinsand schematic equation is illustrative of the last step which is theformation of the ester:

chrysanthemum:monocarboxylio and allethrin, by themselves, inhousehold-type oil sprays" are capable of kill, as well as knockdown ofinsects, such as flies and roaches, if used in sufiicientamount. From apractical, economic viewpoint, this is too expensive. Although theannoyance from flies is removed for aitime when they are no longercapable of flight, an amount of pyrethrins or allethrin sufficient toprovide knockdown is not suflicient to kill. With roaches also, anamount of pyrethrins or allethrin insuflicient to kill is sufl'lcient toactivate them so that they will come out into the open where they can besprayed directly with chemicalfor a kill. To bring down the cost of thesprays, they have'to be fortified either with another toxicant orkilling agent, such as DDT or methoxychlor, for instance, or with asynergist to extend or broaden their action or both.

The scarcity of pyrethrum during World War II stimulated the search forand development of addition materials which would improve the eliiciencyof the pyrethrins. To these addition materials which, of themselves,have little or no value as insecticides, the terms activators,extenders, and synergist's have variously been applied. One of theearliest synergists developed for pyrethrins isN-isobntylundecyleneamide introduced about 1938. Sesame oil of which theactive ingredient, sesamin, was found to be a synergist for pyrethrins,was discovered (U.S. Patent 2,202,145; 1940 at about this Same time. Theknowledge acequired about the structure of sesamin led to the synthesisof related compounds, such, as piperonyl butoxide, piperonyl cyclonene,n-propylisome, and sulfoxide, which are the most commonly used pyrethrinsynergists. Other less efiective synergists are N-(2-ethylhexyl)-bicycloheptenedicarboxamide, polyoxypropylene glycol monobutyl ether ofabout 800 average molecular weight (viscosity, 240 to 260 S.U.S. at 100F.), and the pinene ether of ethylene .glycol.

As in the case of pyrethrum, efforts have been made to extend theinsecticidal usefulness of allethrin. 'Although allethrin currently isnot as costly as pyrethrum, on the other hand it is not capable of beingas highly activated or synergized by the available pyrethrum'synergists, as is pyrethrum.

Our new ester is more effective than are other pyrethrum replacements inactivated or synergized compositions, as evaluated by standard testsagainst household pests, for instance. It is more effective also againstectoparasites of animals; lnaddition, it can be used to protect foodproducts such as wheat and corn from insect attack. The number ofchemicals available for this use is quit'elimited because'of the dangersfrom residues left in the final food product consumed by humans andother animals. Because of the freedom of our new ester; cyclethrin, frommammalian toxicity, it can be used to advantage for these purposes.

, 4 STEP 3 Ethyl 4-(2-cyclopentenyl)-3-ketobutyrate is made by reactionof diethyl carbonate with the 2-cyclopentenyl acetone product of Step 2.

on =on I AHCHQCQCHS'i'CI IOCOCIHIfi Hz-CH: i

z-eyelopentenyl diethyl-t acetone carbonate CH=CH fi H vononzooonioocnn. on,- H,

; ethyl -(z'cyclopentenyw 3-ketobutiyrate STEP 41 The synthesisof ourester, cyclethrin, involves a numher of steps, the reactionsjof whichcan be illustrated by the following scheme of equations:

STEPl Hydrogen chloride is caused to add to cyclopentadiene, which is arelatively inexpensive starting material, to form 2-cyclopentenylchloride:

2-eyclopentenylacetone is formed by the reaction of sodium acetoaceticester with the Z-cyclopentenyl chloride from Step 1, followed by ketoniccleavage.

CH=CH 0-4313; CH=CH COCH2 on=en coon: sodium Mn-CH, CH( J CHOH 1ethoxide I I C H- CHr-C a" O=O-CHOH CH: CH: CCHa uni-on, CODE; 55 311. I1

W Sodium B-(Z-cyclohentenyDfi- 2-(2-eyc1opentenyl)-3-methy1- pentenylacetochloride acetic hydrox yhexane 2,5-dlone cyclopenteu--ol l-oneester CH=OH COCH CH=CH H ("2H 3 NaOH first; 7H CH 00031 E OH STEP 6 Ithen 1 0 a 3+ 60 7 Finally, the cyclopentenolone product of StepS 1S000E; CHT'CHQ CO1 treated to form the ester of dl-cis and dl-transchrysanalpha-(2-cyclo- 2-cyclo euten l acetone mummy acetoacem P ythemummouocarboxyhc acid, preferably through the an ester hydride.

( 9 0 0 a t a v G\ CHrg 7 05 J t ('JHr-PJ a l/CHCOOH-I-HOH l CH= CH---)l/CHCOO?H I (JH -CH 11 -|H H (J -041311 ?}H CH; CH:- Ha (BB 7 CH:CHr-CHI C(CH3)I HHa):

chrysanthe z-(z-cycloeentenyncyelethrin mummonocar-3-methyl-2-cyelcpenten- 4-ol-1-one n g ho xylic acid Pyruvic aldehyde isreacted with the ethyl 4-(2-cyclopentenyl)-3-ketobutyrate product ofStep 3 in the presence of dilute aqueous alkali metal hydroxide to forml6'-(2 -cyclopentenyl)-3-hydroxyhexane 2 ,5 dione. The ester issaponified to the sodium or potassium salt of the corresponding acid,which salt in turn condenses with the pyruvic aldehyde.

CHI-CH V endmoocmo+noooom- Hr- H: H

4-(2-eyclopentenyD-3- pyruvte ketobutyric acid 3 aldehyde 03 011 v Ihnomo-omonon eni l-oo, '1 CH2- H2 0-(2-cyclopeutenyl)-3-hydroxyhexane-2,5-dione v STEP 5 The product of Step 4 is treated with dilute sodiumhydroxide to form 2-(2-cyclopentenyl)-3-methyl-2-cyclopenten-4'ol-1-one.

5 Cyclethrin isa-"mixtureof isomers, including four racemic forms oreight optical and geometric isomers. These isomers have not yet beenisolated and evaluated.

While it might be possible, on the basis of a graphic representation ofstructure, to regard ournew ester as similar to allethrin except for a2-cyclopentenyl group in a position corresponding to that occupied byanall-yl group in allethrin, such a view would be an oversimplification,unwarranted by the facts. Even were'it possible to employ allethrin as astarting material-for thepreparation therefrom of other compounds-by thedirect substitution of the allyl group, it does not follow that all ofthe products would exhibit the same useful biological activity. Forinstance, according to our studies and information, the following estersofchrysanthemummonocarboxylic acid are inferior in insecticidal activityor value:

(No. 6723) CIBH:

CH: C

l OIL-= CHgO CHO--chrys anthemumyl O C CH,3-metlial1yl-2-methyl-4-oxo-2-cyclopenteny1 chrysanthemumate (No. 6737)O (J-OH;

CQH5CH2-C CH-Ochrysanthemumyl C CH;

3-benzy1-2methy1-4-oxo-2cyclopentenyl chrysanthemumate (No. 6979) C OCH:

CH2=CHCH2C CH-O CHIC/H2O C H1OHOeh1-ysanthemumyl C CH;

6- 3-nlly1-2-methyl-4-oxo-2-cyclopenteny1) -3,6-dioxahexylchrysanthemumate (No. 6980) C0CH C H -=C H 0 H 0 0 11-0 C HzC HaOehrysanthemumyl C CH:

3- 3-allyl-2-metl1yl-4-oxo-2-cyclopentenyl) -3-0xapr0py1chrysauthemumate Biological testing of cyclethrin, unsynergized, revealsthat it is of the same order of effectiveness as furethrin(3-furfuryl-2-methyl-4-oxo 2 cyclopentenyl chrysanthemummonocarboxylate), unsynergized; and that both are equal to allethrin,all unsynergized. It reveals also that those synergists which aresuperior in effectiveness with pyrethrin can also be used as synergistsfor cyclethrin. In general, slightly higher knockdown is obtainable withsynergized pyrethrin than with cyclethrin synergized with the samesynergists.

However, when synergized cyclethrin is compared with synergizedallethrin only one-half as much cyclethrin is required with Sulfoxide"or with n-propyl isome; only one-third as much cyclethrin with piperonylbutoxide and only one-half to two-thirds as much with sesame oilextractives.

Another advantage "of cyclethrinisthat it is even less toric to' mammalson aidirectconcentratiohbasis than is allethrin. According to one 'setoftests, undiluted cyclethrin (95.6 percent purity) has'an LD'50 for ratsin the neighborhood of 1.4 grams per kilogram as compared with 0.34grams per kilogram for allethrin. According to another set of tests, theLD-SO for cyclethrin fed to male albino rats by intubationis 1.78 gramsper kilogram. Fed as a dilution in Bayol D, the toxicity of cyclethrinis much less. For instance, at a concentration of 10 percent by weightin Bayol D, 3.98 grams per kilogram of cyclethrin killed only one ofvfive rats while 2.0 and 1.0 gram per kilogram has allowed survival.Similarly, at a concentration of 20 percent by weightin Bayol D, theLD-50 for male albino ratsis 4.9" grams per kilogram on the basis of theactive ingredient.

For comparison, the LD-50 dose for diluted allethrin at a 10 percentconcentration in Bayol D is 0.90 gram perkilogram and at a 20 percentconcentration by weight in deodorized kerosene. it is 0.92 gram perkilogram for male rats. According to these studies, cyclethrin seems tobe of the order of about one-fifth as toxic as allethrin for rats insingle oral closes on a direct concentration basis, and still less atactual use levels.

Compounds which are useful as synergists in combination with cyclethrinare:

A. Piperonylbutoxide'which'isa technical grade of the3,4-methylenedioxy-6-propylbenzylether of diethylene glycol monobutylether having a structure as represented by the following graphicformula:

O CHgO C:H(O CaHAO C4Ha Compounds closely related tothe above amount toabout 20 percent by weight of the piperonyl .butoxide.

B. Normal-propyl isome which is the-name given to di-n-propyl-2-methyl6,7 methylenedioxy-l,2,3,4-hexahydronaphthalene-3,4-dicarboxylate. Itsstructure can be represented by the following graphic formula:

CHOH: 2O

\ oHoooonn COOCBH7 D. Sulfoxide which is the name given to then-octylsulfoxide of isosaphrole. It has a structure which can begraphically represented as follows:

E. N-isobutyl undecylene amide, having...the..general.

F. Pinene ether of ethylene glycol, having theQem pirical formula:

C H 'OCH CH OH' saw , G. Piperonyl cyclonene, which is a mixture of3-isoamyl-5-(3,4-methylene dioxyphenyl) -2-cyclohexenone and its6-carbethoxy derivative: 7

I. Sulfone, which is the name given 'fone of isosaphrole. i

to normal octylsulomonom J. Synergist 264 which is the number assignedto N-(Z- ethylhexyl)bicyclo-2.2.1-5-heptene-2,3-dicarboximide.

H-co

K. Sesame oil is the name given to the oil from Sesamum indicium ofwhich about 0.25 percent is sesamin. The structure of sesamin can berepresented graphically by the formula:

Of the eleven synergists named, sulfoxide and piperonyl butoxide arepreferred.

Cyclethrin concentrates, containing in addition to cyclethrin otherbiologically active materials such as, for instance, polyoxypropyleneglycol monobutyl ether having an average molecular weight of about 800(known commercially as Crag brand fly repellant); beta-butoxy-beta'-thiocyanodiethyl ether and a mixture of the beta-thiocyanoethyl estersof higher fatty acid having 10 to 18 carbon atoms (known commercially asLethanes); terpene thiocyanoacetates (known as Thanite-IsobornylAcetate); methoxychlor; and a synergist can be used to protect livestockfrom such ectoparasites as flies, lice and ticks. Illustrative of such aconcentrate would be a formulation containing the ingredients in thefollowing relative proportions by weight.

This formulation can be applied directly to cows, for

example, in an amount which is from 0.5 to 2 grams per animal per day;If desired, the concentrate can be diluted with water usually in suchproportion that the diluted concentrate, so called, can be sprayed in anamount from one to four pints per animal per week to protect against flyattack.

Furthermore, a concentrate as of the above formulation, either with orwithout emulsifier, can be diluted with petroleum distillate or waterand be applied as space sprays for knockdown and kill of flies, mothsand the dike; or it can be applied to agricultural crops to protectagainst insect attack. Specifically, beans, corn, cabbabe, apples andapple trees, grapes and the like can be protected from forms, beetles,aphids and spiders. Similarly, it can be sprayed on such surfaces as theinterior of grain bins or elevators to kill insects attacking cerealgrains, or it can be applied directly on cows or other live-stock toprotect against fly attack. Still further, these same concentrates whendiluted either with oil or water can be applied to such packaged goodsas cereals or flour in cloth or paper containers to protect againstinsect penetration and infestation. Good results have been obtained withcyclethrin concentrations having the following compositions:

Parts by Weight Formulation Formulation cyolathrln plperonylbutoxlde...Fly repellant 1 (Orag).. 1

petroleum distillate bitleaka e-up l Polyoxypropylene glycol monobutylother; aver. molecular weight about 800. I

Panssmuznn SPRAY Parts by weight Cyclethrin 0.01 to 6.0. Synergist 0.05to 10.0. Toxidant 1 0.0 to 6.0. Polypropylene glycol monobutyl ether 0.0to 55.0.

*Viscdslty at c., 250 s.u.s.; av. mol. wt. s50. Freon 11 Freon 12.

Our new insecticide, cyclethrin can also be used in dry formulationsespecially adapted for protection of cereal grains and flour againstinsect infestation in combination with inert dust-type carriers, such aswheat flour, kaolin,

talc, pyrophyllite, diatomaceous earth, Kieselguhr, bentonite, groundwalnut hulls, ground sawdust and the like.

Illustrative of a suitable composition for "thispurpose isa formulationas follows:

GRAIN Pnorac'rm Inert dust-type carrier, remainder to make 100 parts.

The following examples are illustrative. 7

Example 1 Part (a).--Anhydrous hydrogen chloride was added to a mixturecomprising 99 grams (1.5 mols) of monomeric cyclopentadiene in 380 gramsof carbon tetrachloride. The mixture was maintained at a temperature'of'O' C. during the addition which was continued for a period of aboutone hour until a gain in weight ofabout 58 grams was obtained. After thecarbon tetrachloride .had been distilled ofi at atmospheric pressure,there was obtained 138 grams (1.35 mols) of 2-cyclopentenyl chloridedistilling at a temperature of 52 C.53 C. at an absolute pressure of 100millimeters of. mercury. The yield was 90 percent of theory.

Part (b).Three hundredsixgrams of sodium-ethoxide (4.5 mols) in the formof 1570 grams of a 19.5 percent solution in ethanol were added graduallyto 650 grams (5 mols) of ethyl acetoacetate with stirring over a periodof 30 minutes. The mixture was maintained at a temperature of 20 C.during the addition. After the mixture had been stirredforanadditionalperiodofione hour at 20 C., it was heated to atemperature of 50 C.

and 459 grams of 2-cyclop'entenyl chloride (4.5 mols) were added over aperiod of 1.5 hours. To complete the reaction, the mixture wasmaintained at its refluxing temperature at atmospheric pressure for aperiod of 3 hours.

At the end of this time ethanol was removed from the mixture bydistillation at atmospheric pressure to a kettle temperature of 125 C.The residue, which contained ethyl 2-cyclopentenyl-acetoacetate, wascooled to 20 C. and 2500 grams of aqueous sodium hydroxide percent; 6.25mols) were added over a period of 30minutes. To complete the ketoniccleavage of the compound the mixture was stirred for a period of 4'hours' while the temperature was maintained at 20 C. Next, 400milliliters of aqueous-sulfuric acid (50 percent) was added to reducethe pH of the mixture to 3.5. The mixture was treated with 200milliliters of benzene and a distillation carried out at atmosphericpressure using a rectifying column fitted with a decanter of 175milliliters capacity filled with benzene. During the distillation, atotal of one liter of water was fed gradually into the vapor line justbefore the condenser. The lower layer in the decanter was continuallyremoved while the oil in the decanter was returned as reflux to thestill. This procedure was continued until the bead temperature reached68 C. with the result that all of the ethanol was removed from thesystem while all the 2-cyclopentenylacetone product remained in thestill.

Upon distillation of the oil in the residue, to which was added the oilin the decanter, there was obtained 440 grams of 2-cyclopentenyl acetonehaving the following properties: boiling range at an absolute pressureof millimeters of mercury, 66 Cato 68 C.; specific gravity (/20), 0.940.Analysis of the distilled product for ethyl acetoacetate by the sodiummethoxide procedure gave avalue of 8.3 percent by weight.Analysisforketone by the hydroxylamine procedure gave a cyclopentenylacetone content of 89.1 percent by weight after correction for the ethylacetoacetate content. Because the boiling points of 2-cyclopentenylacetone and ethyl aceto- 10 acetate lie very close; separation of'the'two compounds 'by fractional distillation is not readilyaccomplished. Upon removal of the ethyl acetoacetate from the2-cyclopentenyl acetone, by saponification, the pure ketone had aspecific gravity (20/20) of 0.934. and a refractiveindex (n of 1.4543.The yield of 2-cyclopentenyl acetone was 72 percent based on the2-cyclopentenyl chloride, corresponding to an efliciency of 72 percent.

-Part '(c).-Diethy1 carbonate (2240 grams; -19 mols) was charged to adistillation kettle fitted with a refluxing condenser, and heated'undera reduced pressure of millimeters of mercury absolute at its refluxivetemperature. Sodium ethoxide 185.6 grams; 2.73 mols) in the form ofa19.3 percent solution in ethanol (776.4 grams) was fed into the kettleover a period of 2 hours while ethanolwas being continually distilled.The total'distillate collectedwas 1033 grams. After all the ethanolsolvent had been removed,'leaving a suspension of sodium ethoxide in thediethyl carbonate in the still kettle, 340 grams of 2-cyclopenteny1acetone (purity, 91.7 percent; 2.51'rnols) were fed over a period of twohours while the distillation-was continued as before to remove ethanol.The-total amount of distillate removed in this step was 289 grams. "Theresidue was then cooled to 25 C., acetic acid (1-74'grams; 2.9 mols)added, which was followed by the .addition of 620 milliliters of waterto dissolve the sodium acetate. The-oil layer was separated anddistilled rapidly under reduced pressure. There was obtained 400 gramsofethyl 4-(2-cyclopentenyl)-3-ketobutyrate having a boiling range of 100C. to 155 C. at

an absolute pressure of 5 millimeters of mercury. 'By titration'withsodium methylate in pyridine the purity was found to be 94.6 percent.Analysis of the mid-fraction (183 grams) showed that it contained 82.4grams of product. The yield based on the 2-cyclopentenyl acetone was 85percent.

1 art (d) .Eight hundred nineteen grams of ethyl4-(2-cyclopentenyl)-3-ketobutyrate, having a purity of 93.1-percent(3.89 mols) were added dropwise over a period of one hour to 2180 gramsof a well-stirred aqueous solution of sodium hydroxide (9.5 percent;5.18 mols) maintained at a temperature of 20 C. to 25 6. At the end of16 hours, the solution was neutralized to a pH of 7.5 with carbondioxide.

Fifteen hundred grams of an aqueous solution of pyruvic aldehyde (22.4percent; 4.67 mols) which had been neutralized to a pH of 7 with 26grams of sodium bicat- 3-hydroxyhexane-2,5-dione which was found byanalysis to have a purity of 75.8 percent. The yield was 74 percentbased on the ethyl-4-(2-cyclopentenyl)-3-ketobutyrate.

Part (e).Three hundred sixty-eight grams of 6-(2-cyclopentenyl)-3-hydroxyhexane-2,S-dione having a purity of 75.8 percent(1.42 mols) was fed dropwise over a period of 30 minutes to 3312 gramsof a 2 percent aqueous sodium hydroxide, vigorously stirred andmaintained at a temperature of 20 C. to 25 C. After a period of 4 hoursallowed for completion of the'reaction, the mixture was saturated withsodium chloride and four successive extractions were made, each withone-liter portions of diisopropyl ether. Thefour extracts were combined,neutralized with 2 grams of acetic acid and distilled under reducedpressure.- There was obtained 139 grams of a product fraction whichdistilled from'a temperature of C. at an absolute pressure ot-2.5

millimeters of mercury to a temperautre of.170 C. at anabsolute-pressure of millimeters 'of mercury. This product was found byanalysis to contain 72.8 percent of 2-,( 2-cyclopentenyl) -3-methyl-2-cyclopenten-4-ol-1-one. The yield was 40 percent. 7 Part(f).-A mixture was formed-of 275 grams of 2-(2-cyclopenten)-4-ol-1-one(purity 70.8 percent; 1.094 mols), 156 grams of pyridine and 0.9.05liter of ethanol. To this mixture was added, a solutionof 183 grams ofsemicarbazide hydrochloride (1.64 mols) in 220 milliliters of water. Themixture was allowed to stand 16 hours and at the end of that time thecrystals of the semicarbazone which had formed were filtered ,-andwashed with 4 liters of water to remove chloride. Upon crystallizingthesemicarhazone from ethanol, 181 grams ofcolorless crystals'ha-ving amelting point of 208 C. to 210 C. were obtained. The yield of the puresemicarbazone of 2- (Z-cyclopenteny'l) -3-methy1-2-cyclopenten-4-ol-1-one was 71 percent. v

A mixture of 181 grams of the puresemicarhazone (0.77 mol), 1.6 litersof water, 1.6 liters of diisopropyl ether and 1047 grams of potassiumacid sulfate (7.7 mols) was stirred at 60 C. to 65 C. for a period of2.5 hours. By that time all ofthe semicarbazone had dissolved whichindicated that hydrolysis had taken place and was complete. The aqueouslayer was separated and extracted three times with 200 milliliterportions of diisopropyl ether-.- The three extracts were combined withthe oil layer from the hydrolysis and the whole washed with 200milliliters of saturated sodium chloride solution. Upon distillation ofthe ether solution there was obtained 101 grams of 2-(2-cyclopentenyl)3-methyl-2-cyclopenten4ol-l-one characterized by the vfollowingproperties: boiling point at an absolute pressure of 1 millimeter ofmercury, 131 C.; refractive index (22 1.5350; purity (by analysis forhydroxyl content), 96.7 percent. The yield based on the semicarbazonewas 84 percent, with credit being taken for 17 grams of productcontained in the mid-fraction and column holdup.

Part (g) .-A-mixture of 92 grams of Z-(Z-cyclopentenyl 3 methyl 2cyclopenten 4 01,- 1 one having a purity of 96.7 percent (0.5 mol), 168grams of chrysanthemummonocarboxylic anhydride having a purity of 94.8percent (0.5 mol) and 119 grams of dry butyl ether was refluxed at atemperature of 165 C. for a period of 4 hours. The solution was dilutedwith 42 grams of butyl ether and washed successively with 263 grams of7.6 percent aqueous sodium hydroxide (0.5 mol), 0.25 liter of 2 percentaqueous sodium hydroxide (0.125 mol) and 0.25 liter of water. The Washeswere each extracted in sequence with a single 0.1'liter portion ofdibutyl ether to minimize loss of product. The washed oil and extractwere combined, stripped of volatile material at a kettle end temperatureof 80 C. at a reduced pressure of 5 millimeters of mercury, absolute,and thereafter stripped with steam. There was obtained 162 grams ofresidue product characterized by the following properties: refractiveindex (n 1.5120; specific gravity ('20/20 (3.), 1.033; purity by theethylene diamine method, 87.1 percent; acid content, aschrysanthemummonocarboxylic acid, 0.1 percent; andchrysanthernummonocarboxylic anhydride content, 0.2 percent. The yieldbased on the reactants was 88 percent, with credit being taken for 4.3grams of product consumed in analysis of the reaction mixture foranhydride content.

A number of formulations were prepared in which cyclethr-in preparedaccording to a procedure the same as or similar to those described inExample 1 was tested for efficacy in admixture with a variety ofcompounds having a synergistic effect. These formulations were tested bythe Feet-Grady method (Olficial Method of the Chemical SpecialtiesManufacturers, Association). The results of these tests together withthe comparison tcst'results obtained-with the Official Test Insecticide12 (herein referredto as OT I) Y and with allethrin formulationssimilarly synergized are given in the-following examples:

LARGE GROUP FEET-GRADY RESULTS Percent OTI Difference No. 0t PercentKnoeir- Formulation Tests down,

' 24 Hrs. 10 min. Kill Knockdown 1 A. cyclethrin 61.3 91.2 +25 2. 8 13.,allsthrin- 5 40. 0 90.0 +4 4. 0 OT! 35. 5 94. 0

These test results show that the plus value for kill and the minus valuefor knockdown of the synergized cyclethrin compared with: OTI are betterby 21 and 1.2 percentage points, respectively, than a similar comparisonof synergized allethrin with OTL Example 3 Formulation r. a 0T1cyclethrin. milligrams 3...... 50 85 alletllrin,milll mm 50 pyrethrlns,milligrams 100 n-octyl sulfoxide of isosafrole, milligrams 250 250deodorized kerosene fraction, milliliters 100 100 100 40 7 LARGE GRO PFEET-GRADY RESULTS Percent 0T1 Difference No. of Percent KnockFormulation Tests Kill, down,

24Hrs. 10 min. Kill Knockdown A. eyclethrin 6 74. 9 96. 5 +38 +1. 4 B.allethrin 6 37. 2 90. 6 0 4.5 OT 8 37. 0 95.1

These test results show that the plus values for kill and knockdown ofthe synergized cycletin-in compared with 0T1 are better by 38 and 5.9percentage points, re spectively, than a similar comparison ofsynergized allethrin with OTI.

' Example 4 Formulation cyclethrin, milligrams allethrin, milligrams.pyrethrins, milligrams n-propyl tsome, milligrams deodorized kerosenetraction, milliliters By n-propyl isome is meantdi-n-fpropyl-amethyl-fiJ-methylenedioxy-1,2,3,4,-hexahydronaphthalene-3,4icarboxylate.

' deodorized kerosene fraction, milliliters assess? 13 The results ofthis test show that the plus value for kill for synergized cyclethrincompared with OTI is better by 18 percentage points thin a similarcomparison of synergized allethrin with OTI; while the knockdown is onlyslightly less favorable by 1.9 percentage points.

Example Formulation A B OTI cyclethrin, milligrams allethrin,milligrams" pyrethrins, milligrams sesame oil, milligrams deodorizedkerosene fraction,

LARGE GROUP FEET-GRADY RESULTS The results of this test show that thevalue for kill of the sesame oil-synergized cyclethrin, even thoughminus compared with OTI, is better by +7 percentage points than asimilar comparison of synergized allethn'n with OTI; while the knockdownis only slightly less favorable by -1 percentage point.

{Chemical identification: N-(hexoxyethoxypropyl) bieyclo 2.2.1-5-heptene-2,3-dicarboximide.

LARGE GROUP FEET-GRADY RESULTS 7 Percent OTI Diii'erence No. of PercentKnock- Formulation Tests down,

24 Hrs. 10 min. Kill Knockdown A. cyclethrin 5 46.6 94. 2 +13 +0.2 B.allethrim- 5 31.4 92. 1 3 -1.9 OT 8 34. 3 94.0

The results of this test show that the plus values for kill andknockdown of the synergized cyclethrin, compared with OTI, are better by16 and 2.1 percentage points, respectively, than a similar comparison ofsynergized allethrin with OTI.

Example 7 Formulation cyclethrin, milligramsallethrin, milligrams-.pyrethrins, milligrams synergist 264, milligrams.

Chemical identification: N-(2-ethy1hexyl) bicyclol2.2.11-5-heptene-2.3-dicarboximide.

LARGE GROUP PEET-GRADY- RESULTS Percent OTI Difference No.01 PercentKnock- Formulation Tests Kill, down,

24 Hrs. 10 min. Kill Knockdown A. cyele'thrin 5 31.8 93.0 +7 -i.5 B.allethrin--- 5 '29.!) 90.7 +4 -3.8 OTI s 24.9 94.5

Example 8 Tests were carried out on a formulation containing cyclethrinas an oil-base livestock spray in comparison with a commercial oil-baselivestock spray containing pyrethrins. The proportion of ingredientspresent in the formulation was as follows:

Formulation cyclethrin, milligrams pipcronyl butoxide, milligramspolyoxypropylene glycol monobutyl ether- Spray oil added to make upsolutions to a volume of milliliters.

The tests were carried out on dairy cattle in a South Atlantic State andten cows were used for treatment by each formulation. The cows weresprayed twelve times and the sprays were applied at intervals of threeto four days at a rate of two ounces per animal. The sprays were appliedin mid-afternoon and counts were taken at noon on the following day, ofhorn flies (=h); stable flies (=S); and house flies (=H). The ratio ofthe fly species in total population was 50, 20 and 30 percent,respectively, for horn flies, stable flies and house flies.

The results of these tests 1n terms of repellency are glven 1n thefollowing table:

Percent Repelleucy at Repellency Fly Species for Period,

. Average 24hr; 48hrs. 72hrs.

65. 7 55. 4 31. 8 50.9 44.4 41. 7 3.0 29. 7 Spray A (pyrethrins) 50.941. 2 21.5 37.9 40.0 35.3 43.1 39:5 90. 0 76.8 47. 8, 71. 5 71. 5 63. 850. 2 61. 8 49. 7 50. 0 27. 7 42. 5 Spray B (pyrethrins) 71.1 35.8 40. 549.1 57. 3 44. 5 48. 8 50. 2 88. 0 88. 1 74. 6 81. 6 74. 2 63. 0 52.063. 1 60.0 43.0 0 34.7 Spray 0 (cyclethrin) 74. 9 47.1 52. 3 58.1 65. 241. 4 55. 5 54. 0 84.7 88.6 93. 7 89.0

The above values for percentage repellency are based on the number ofcounts taken, as follows:

15 According to these tests, the synergized eyclethrin forrnulation asan oil-base livestock spray is shown to be more effective in repellencyagainst horn, stable and house flies than commercial formulations ofsynergized pyrethrins. It is to be noted that spray C is superior to'spray B, and at the same time cheaper than spray B and,

accordingly, spray A. Thus, at current prices for the ingredients of therespective formulations, this increased effectiveness with synergizedcyclethrin is obtainable without increase in cost.

Example 9 Formulations employing the same proportions of ingradients asthose of Example 8, except that deodorized kerosene was substituted forthe spray oil of Example 8, were made as follows:

FORMULATION, SERIES 2 Formulation Oyclethriu, Allethrin, Sulfoxide,

milligrams milligrams milligrams The results in terms of the dosagerequired to kill 50 percent of the roaches in 24 hours are given in thefol- Formulation T1, A l B l 0 210 lowmg table plperonyl butoxide,milligrams 200 120 120 RESULTS SERIES 2 pyrethrins, milligrams 100 25 15Cralggly Be ilelllenh mllliliters-. 1g Milligrams cyc e 1r n, m lgrams 1f 1 Deodorized kerosene to make 100 milliliters of 2 Forum l l'fl )50,solution. 24 hours y yp pv glycol uty e A m u h E (cyclethrin) F throughH (cyclethrln). 4. 5 I through M (allethrin). 3 LARGE GROUP FEET-GRADYTEST assume FOR CON 0 Nthrouzh P a11ethrm TROL OF FLIES I fi w ri i fige 0T1. In both series, cyclethrin was synergized more effec- Formulatmn3 ferelce trvely than ailethrm. In the case of allethnn, only onees S a5 '10 ours 3m half or less of the amount required unsynergized was111111 min millsaved by synergizing it, whereas in the case ofcyclethrin it was possible to save from two-thirds to four-fifths of the6 88.1 90.2 95.2 67.9 +31A'l s 87.0 92.6 96.0 72.3 +36 All amountrequlred ulsynergzed 6 80.8 85.4 93.6 70.3 +34 AA 10 91.5 93.9 94.9 36.7B 40 Example 11 The efficacy against the bean aphid on nasturtium plantswas determined for cyclethrin, alone, and cycle- Accordmg to i tests ffi effectlve, m thrin synergized with sulfoxide (n-octyl sulfo'xide ofisosltnocltdown and kill as spray B, w 1e at e same time afrole), andsynergist 6266 (Nmafoxyethoxyprppynbb expenslve'cyclo-[2.2.ll-5-heptene-2,3-d1carbox1mide). Similar tests were also madewith allethrin.

Example 10 The elficacy against the German Roach was determined 0 vAneth'rm' oycle'thrm, sulfoxid'ey synergisi f0! cyclethrin alone,-andfor cyclethnn in combination Formulation Milligrams MilligramsMilligrams t s zss,

- a 1 grams with sulfoxide (n-octyl sulfoxide of isosafrole) assynergist.

FORMULATION, SERIES 1 Oyclethrin, milligrams Formulation Allethrin,

milligrams lllll 1 In addition, each of the solutions contained 0.02milliliter of Triton;

5 milliliters of acetone, and the whole made up with water to a totalvolume of 0.1 liter.

A second series of tests were run employing the following formulations.

In addition, each of the formulations contained 10 milliliters ofacetone, an amount of emulsifier which was 10 percent oi the totalweight the following table:

allethrin, milligrams" cyelethrin, milligramspiperonyl butoxide,

grams deodorized kerosene given'in the following table:

aesspa'r scale. The results in terms of the LD-50 and the LD-95 for a24-hour kill were as follows:

Milligrams for kill within'24 hours Formulation LD-50 LD-95 A through E(allethrin) N through l? (cyclethrin).

'1 through V (cyciethrin). W through Y (allethrin) Z through BB(eyclethrin) According to the results of these tests, cyclethrin isrendered more effective by the synergists than is allethrin, by aconsiderable factor.

Example 12 A comparison was made of cyclethrin and allethrin againsthouseflies in large group Beet-Grady tests. The results, which are theaverage of five tests aregiv'eu in Concen- Percent Percent Materialtration knockdown.

24 Hours 10 minutes rauethrmfln 20o, 48.6 7 V 97.5 -Gyclethrin 200 44. l96; 6 Allethrin- 100, 25. s 7 p 91. 4 -Cyclethrin 100 26. 6 89. 6Allethrim. 50 14. 7 83.1 --Cyclethri1 1 50 16.4 7 7 78. s

111 milligrams per 100 milliliters of solution in deodorized keroseneira ction.

An analysis of the variance of the above results shows no significantdifference in the performanceof valiethrin and cyclethrin when usedunsynergized against house Example 13 ..Synergized cyclethrin wascompared with synergized .zallethrin against housefiies in large-groupFeet-Grady :tests. The synergists were piperonyl butoxide (3,4-:methylenedioxy-6-propyl) benzyl butyl diethylene glycol -ether),synergist 6266 (N-(hexoxyethoxypropyl)bicyclo-12.2.l-5-heptene2,3-dicarboximide) sulfoxide (n-octyl sul- -ioxide ofisosafrole) and n-propyl isome (di-n-propyl- 2-methyl-6,7-methylenedioxy-1,2,3,4-hexahydronaphthalene-3,4-dicarboxylate).

Formulation A1 A2 B2 01 02 D1 2 milligrams synergist 6266, milligramssulfoxide milligr n-propyl isome, milli- I fraction, milliliters.- 100 i100 The results which are theaverage. of four tests are A2 (cyclethrin,

7 B1 (allethrin,

i fraction.

Percent Percent Formulation 00k- 1 24 Hours down 10 Minutes A1(allethrin plus piperonyl butoxide) 40. 0 90.0 A2 (eyelethriu pluspiperonyl butoaide) 61. 3 91. 2 B1 (allethrm plus synergist 62fi6). 31.492. 1 B2 (oyclethrin plus synergist 6266) 46. 6 94. 2 Cl (allethrin plussulfoxide) 37. 2 90. 6 O2 (cyclethrin plus sulfoxide)- 74. 9 96. 5 D1(allethrin plus n-propyl isome). .42. 3 92.0 D2 (cyclethrin plusn-propyl isome) 63. 4' 92. 8

The amountof-unsyne'rgized. cyclethrin and unsynergized allethrin thatwould be required 'to 'givethe same percent kill and knockdown as wasobtained above. the synergiz eci material can be estimated by'plottinggraphically the resultsofExainple 12 and taking'Tofi from the curvesthus obtained the amounts corresponding to'thekil-ls and knockdowns forthe syner'g'iZejd material above. The amounts thus estimated are givenin the following table:

Equivalent amount (milligrams) toxicant for the same effect Formulation1 24 hour kill 10 minute knockdown alleth'rin cyciethrin cyclethrinallethrin Al (allethrin, 25; piperonyl butoxide200) piperonyl butoxide200) olfiallethrin, 50; sulfoxide,

D1 (allethrin, 50; n-propylisome, 250) L.

D2 (cyclethrin, n-propyl isome, 250) 'Values in milligrams are given per100 milliliters 5i deodoiiz edkerosene .j The ratio of. effectiveness ofthe synergizedto 'synergized toxicant (allethrin, synergized .v...unsynergized; cyclethrin, synergized v. unsynergized) based on theforegoing values; are as follows:

Kill Knockdown Synergist allethrin cyclethrin allethrin cyclethrinPiperonyl hutoxicle 6.4 14.0 w I 3.9 Synergist 6266 I 3.7 6.8' '3. 6 4.71 Sulfoxide,... 2. 9 12. 4 i. 9 -3. 6 n-Propyl-iso 3. 5 :7. 6 2. 1 2. 2

Average 4. 1 10. 2 2. 7 3. 6

According to the above results, cyclethrin in overall performance is tentimes more effective synergized than unsynergized, as comparedwithallethriu in overall .per-

' formance which is only four times more eflective synergized thanunsynergized. For knockdown alone,cycle thrin isfour times moreefiective synergized than linsynergized, whereas allethrin, forknockdown alone,.is

only three times moreetlectivesynergized. than unsynergized.

Example 14 Tests were conducted on the common housefly. using cyclethrinin aerosol formulations according to the 0fficial specifications of theStandard Aerosol Test Method for Flying Insects. Comparison tests werealso carried out using allethrin. Equal parts of dichlorodifluoro-Results in terms of'50 percent isac of dead larvae rweretaken afterafllhouqexposure period. Dosage series testswere conducted and resultsplotted on -lo'g probability paper. -l'ethaltdose (LB-50) were asfollows methane (Freon 11) and trichlorofluoromethane (Freon '12) madeup 85 parts by weight of each of the formulations. The remaining 15parts by weight of ingredients making up the formulations were asfollows t 066582 um H l 1 1 m a m ,s i 8 8 r em a W6 W fimvn S M I HT.r1 .B C e ahmmm a 1 Sf u :m 1 003 m i am w m D m. m g u H s u n n a n nm M m T m .m m m t 0 6 5 m m u m mm W a u r mm m u 0 mm. mm n n u 8 v0.O m m m m n n a t .m n m N am ma a m hi) I v h i e S F m n an e mmmmm m1 t a mr r y Y mm mmemkm a 0 l o e. w wnwmmm t v 1 8 0 6 5.6 6 e n m n maaa eaeanaaam mm M mm m wmmmmw t a a l .gg gang wan v m n e e unw uu a"a m m m am m mmmmmm 1.... O u i when tee a eemmmmwmmmmw mm F m M v 1AmnLPm MD zaaa iaeaeae W M l. i m M M B 709840241505 t8 1 S 11 1 .1 1 1p n e we m m mwmmm me mm m m m mm mm m o m B m m Mm mm me u n m Mw r m ee 19 n a DH 8T 246134535213 u V5 0 n .H mm Mmm mm n m mm m Mm um w V. nd mm m m mm m D n m m H mm PB n m. m m AH 112 323 4433 m m mT w W m m mwe R m m m m we b a n 2 2 tg Y Om w 6 v n r b u e T mre b w o m m D R nu m 0d m t s n mm M y 3025969369395535 m E m 5 LU T 03000 n H m G a maennaemennwnmaww fan a m Pm D u m y t e d m ,e a D u mmt E Pndw um m w.u M m 0 u b E a 7 S S. e t m 4 4 I 4 4 4 WW r t saennesasaaessne w m. sw m M@ m 0 0 we a o 0 w w P mm mnmmaaewwnwwamww mm m m m E t s a mg m mn mwm me a m m m h a n .1 t M .c m R e m.1 .0 a m G 0 .m h e m am WT m Wa a m u. E 1 toa o m 7 e m T c G n T .m w m W c m n R m mm n 0 w n an Mm m a w l m a a n mm m nm M min 6 mn Mm 0 w C 0 a e 6 0 l F 1 C S S d wn c TN A m m e m m r sw mm mnm T Example 16 For'purposes of com- In:preparing' the fonnulations,

is alle thrin.

tThe tqxieity to rice weevil determined for cyclethrin alone, andcyclethrin syner ed with sulfoxide, piperonyl butoxide and sulfone.parison similar t6Sts::.W8l8 .made. with allethrin, unsyner- 1 andcyclethrin synergized with synergist MGK-264 (N- 2-(ethylhexyl) bicyclo[2,2,11-5-heptene 2,3 dicarboxirnide) and synergist 6266(N-hexoxyethoxypropyl bi- Accordihg to the foregoing results cyclethrincyclo-[2,2,1]-5-heptene-2,3-dicarboximide). Similaretests p were also mmwithauethrin and pyrethfinx V vated by synergists 2 64 and 6266to agreaterextent than Preparation of formulations and spraying of plantswas done by the method employed in evaluating cyclethrin on bean aphid(Example 11). Two bean plants were used per concentration. After plantshad been sprayed and were thoroughly dry, each plant was enclosed-in aspherical screened cage in which four third instar'larv-ae had beenpreviouslyplaced. Test plants and insects were kept under fluorescentlightat room temperature "Counts gized and synergized.

the active ingredient or active ingredient plus synergist was dissolvedin acetone. An inert dust, in this case wheat dust, was then added tobring the total weight to 100 grams. The materials were then thoroughlymixed to insure uniformity and the acetone allowed to evaporatecompletely from the mixture. The formulation was again thoroughly mixedon a ball mill for one-half hour. The formulations are given in thefollowing table:

Example 18" Material A B O D E F G H Cyclethrin, milligrams 600 100 100100 Aliethrin, mi1ligrams. 500 g 100 100 100 Pi ronyibutoxide,mlliigrams1,600 1,600 B oxide, milligram 1,600 1,600 Sulione,miiligrams H 1,6001,600 Inert diluent (wheat dust) grams 99.5 99.5 98.3 98.3 98.8 98.398.3 98.3

The above formulations were placed in four ounce bottles containing twoounces of wheat and the contents Formulation A B OTI mixed by shakingfor one-half hour. One hundred adult rice weevils were then introducedinto each bottle and cyclethrin, milligrams 84 84 allowed to feed for aperiod of one week. Mortality g g g g l fmj counts were taken at the endof this exposure. Dosage Fly repellant, milliliters 1o 1o sen'es testswere run and the results plotted on log probkemsene, mlmliters abilitypaper.

The results for seven day mortality in terms of lethal dose for 50percent kill were as follows:

. Dosage required for 50 percent Formulation kill within seven days,

milligrams A (cyclethrin) 500 B (allethrin) 260 C (c clethrin) 70 D(cyclethrin) 60 (cyclethrin 52 F (allethrin) 62 G (allethrin) 68 H(allethrin) 51 According to the foregoing results, cyclethrin, althoughonly one-third as effective as allethrin when used alone, is activatedor synergized to a greater'degree than is allethrin by the synergistsemployed. Under actual use conditions, both allethrin and cyclethrinwould be used with synergists because of the prohibitive cost of thesecompounds if used unsynergized. Cyclethrin, because of its freedom frommammalian toxicity, has the advantage that it can be used to protectgrain products.

Example 17 Another use for cyclethrin. indicating its wide range ofusefulness is as a larvicide for the control of mosquito larvae. Inlaboratory tests allethrin and cyelethrin alone, or each with synergistsulfoxide were stirred into 100 milliliters of water containing 20 thirdinstar larvae of the yellow fever mosquito, Aedes aegypti L. Results forthe number of dead larvae were taken 48 hours after the larvae were inthe water medium. Data shown below indicate the effectiveness ofcyclethrin compared with allethrin.

Dosage Required for 60 Eercent Formulation Kill 13-60) in 48 hrs., partsper million Aliathrin 0, 08 Cyolnthrin 0, 07 Allethrin+sulioxide l 0.046 Cyclethrin+sulioxide 0. 043 Untreated checks 0 1 1 part nllethrin+5parts sulioxide. 1 part cyelethrin+6 parts suiioxide.

LARGE GROUP PEET-GRADY TEST RESULTS Percent OTI Diflerence No.0i PercentKnock- Formulation Tests down,

24 Hrs. 10 min Klll Knock down A. cyelethrin 84 96.8 +40 +0.3 B.allethrin 3 73. 2 98.1 +29 +1.6 OTI 44.0 96.5

CH=CH l HCHzCOCHzCHOHOOCHs 2. As a composition of matter,2-(2-cyclopentenylI-3 methyl-2-cyclopenten-4-ol-l-one, represented bygraphic formula:

References Cited in the file of this. patent UNITED STATES PATENTS2,661,374 Schechter et al. Dec. 1, 1953

2. AS A COMPOSITION OF MATTER,2-(2-CYCLOPENTENYL-3)METHYL-2-CYCLOPENTEN-4-OL-1-ONE, REPRESENTED BY THEGRAPHIC FORMULA: